Role of IRAK Signaling in Myelofibrosis


John Mascarenhas, MD, and Ruben Mesa, MD, share insights on the role of IRAK signaling on the disease biology of myelofibrosis.

John Mascarenhas, MD: What is the role of other aspects of the biology of disease? For example, we know that whether you harbor a JAK2 mutation, CALR, or MPL, there's a unified theme of hyperactivity of the JAK-STAT signaling system which ultimately results in a pro-inflammatory cytokine state. But more recently, multiple labs, including Stephen Oh, MD; Angela Fleischman, MD, PhD; Rebekka K. Schneider, MD, and others have shown that other pathways are also relevant to the pathobiology of myelofibrosis. So, pathways involving IL-1 [interleukin-1] and the toll-like receptors as well as the mitosome end up activating NF [nuclear factor]-kappa B, which has been shown by multiple labs to be upregulated and a source of inflammatory cytokines, that then feeds into the system and can feed into JAK-STAT signaling through cytokine receptor engagement. So, it really brings up the next part of this discussion. We have terrific JAK2 inhibitors at our disposal or in late-stage testing, but are there other pathways that are relevant? I would suggest that IRAK signaling, which is integral to toll-like receptor, IL-1, IL-33 [interleukin-33], TNF [tumor necrosis factor]-alpha, and other cytokines that engaged this type of receptor that ultimately results in activation of the mitosome complex, the recruitment of IRAKs, which are IL-1 receptor associated kinases. The ultimate activation of IRAK1 that lead to the up-regulation of NF-kappa B is another focal point or target for therapy. That's where pacritinib, which we've alluded to before, is an interesting drug. This is because it's also a JAK2, FLT3, IRAK1 inhibitor and has been shown to down-regulate that pathway, which likely contributes to its clinical effects in terms of spleen and symptom improvement and perhaps may explain why that drug could be delivered at lower doses. We're learning more and more how the contribution of different mutations and activated pathways lead to disease progression and disease manifestations, but also how therapies in development may be best suited and optimal for use in myelofibrosis due to the fact that they have these off-target effects such as pacritinib and IRAK inhibition.

Ruben Mesa, MD: It's really been a very interesting time as I try to share with folks. I think there are 2 expanding areas. One is regarding additional somatic mutations, and if there is a value to trying to target those in parallel. You mentioned our MPN-RC [Myeloproliferative Neoplasms Research Consortium] 119 study where we are using both IVH2 inhibition with JAK inhibition. As an example, a couple of different pathways are trying to hit both of the pathways. In parallel, there's the approach of these medications that have more than 1 target and that can be relevant. I have been involved with the symptom issue in myelofibrosis. We quantified that the symptoms were there, they were problematic, but then we also learned that they are likely tied to disease biology, at least part of which can be from significant inflammatory cytokines, of which there are a range. Certainly, IRAK1 probably plays a role in that process. Indeed IRAK1 has been identified as possibly playing a role across myeloid malignancies with both some data in AML [acute myeloid leukemia] and in MDS [myelodysplastic syndrome]. With pacritinib, I think it's very interesting because here we have an example where we had initially identified that the therapy, back when it was SB-1518 [pacritinib], and I was involved with its earliest testing. We saw the safety in patients with thrombocytopenia, we did not know that a priori but it was observed, and then it was really subsequent scientific analysis that then found that based on its kinome in terms of how it was acting, that that was a likely mechanism of why there was safety and efficacy in these individuals with marked thrombocytopenia. I use it, if that is a bit akin. Again, there is a parallel story that is evolving with momelotinib where we learned afterward that there was improvement in anemia and that was possibly tied to the inhibition of ACVR1, and that these additional effects which initially were thought to be off-target effects might still have very significant relevance in terms of the spectrum of activity. With pacritinib, that ability to give full dose for individuals with marked thrombocytopenia is pretty important.

Transcript edited for clarity.

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